1. Field of the Invention
This invention relates to devices and methods for measuring optical parameters of a sample, e.g., a sample of tissue in a human body. More specifically, this invention relates to devices and methods for the non-invasive determination of one or more optical parameters in vivo in tissues comprising a plurality of layers.
2. Discussion of the Art
Non-invasive monitoring of metabolites by optical devices and methods is an important tool for clinical diagnostics. The ability to determine an analyte, or a disease state, in a human subject without performing an invasive procedure, such as removing a sample of blood or a biopsy specimen, has several advantages. These advantages include ease in performing the test, reduced pain and discomfort to the patient, and decreased exposure to potential biohazards. These advantages will result in increased frequency of testing when necessary, accurate monitoring and control, and improved patient care. Representative examples of non-invasive monitoring techniques include pulse oximetry for oxygen saturation (U.S. Pat. Nos. 3,638,640; 4,223,680; 5,007,423; 5,277,181; 5,297,548). Another example is the use of laser Doppler flowmetry for diagnosis of circulation disorders (Toke et al, xe2x80x9cSkin microvascular blood flow control in long duration diabetics with and without complicationxe2x80x9d, Diabetes Research, Vol. 5 (1987), pages 189-192). Other examples of techniques include determination of tissue oxygenation (WO 92/20273), determination of hemoglobin (U.S. Pat. No. 5,720,284) and of hematocrit (U.S. Pat. Nos. 5,553,615; 5,372,136; 5,499,627; WO 93/13706).
Measurements in the near-infrared region of the electromagnetic spectrum have been proposed, or used, in prior art technologies. The 600 nm to 1300 nm region of the electromagnetic spectrum represents a window between the visible hemoglobin and melanin absorption bands and the strong infrared water absorption bands. Light having a wavelength of 600 nm to 1300 nm can penetrate deep enough into the skin to allow use thereof in a spectral measurement or a therapeutic procedure.
Oximetry measurement is very important for critical patient care, especially after the use of anesthesia. Oxygenation measurements of tissue are also important diagnostic tools for measuring oxygen content of the brain of the newborn during and after delivery, for monitoring tissue healing, and in sports medicine.
Non-invasive determination of hemoglobin and hematocrit values in blood would offer a simple, non-biohazardous, painless procedure for use in blood donation centers, thereby increasing the number of donations by offering an alternative to the invasive procedure, which is inaccurate and could lead to the rejection of a number of qualified donors. Non-invasive determination of hemoglobin and hematocrit values would be useful for the diagnosis of anemia in infants and mothers, without the pain associated with blood sampling. Non-invasive determination of hemoglobin has been considered as a method for localizing tumors and diagnosis of hematoma and internal bleeding. Non-invasive determination of hematocrit values can yield important diagnostic information on patients with kidney failure before and during dialysis. There are more than 50 million dialysis procedures performed in the United States and close to 80 million dialysis procedures performed worldwide per year.
The most important potential advantage for non-invasive diagnostics possibly will be for non-invasive diagnosis and monitoring of diabetes. Diabetes mellitus is a chronic disorder of carbohydrate, fat, and protein metabolism characterized by an absolute or relative insulin deficiency, hyperglycemia, and glycosuria. At least two major variants of the disease have been identified. xe2x80x9cType Ixe2x80x9d accounts for about 10% of diabetics and is characterized by a severe insulin deficiency resulting from a loss of insulin-secreting beta cells in the pancreas. The remainder of diabetic patients suffer from xe2x80x9cType IIxe2x80x9d, which is characterized by an impaired insulin response in the peripheral tissues (S. L. Robbins, S. L. et al., Pathologic Basis of Disease, 3rd Edition, W. B. Saunders Company, Philadelphia, 1984, p. 972). If uncontrolled, diabetes can result in a variety of adverse clinical manifestations, including retinopathy, atherosclerosis, microangiopathy, nephropathy, and neuropathy. In its advanced stages, diabetes can cause blindness, coma, and ultimately death.
The principal treatment for Type I diabetes involves periodic injection of insulin. Appropriate insulin administration can prevent, and even reverse, some of the adverse clinical manifestations of Type I diabetes. Frequent adjustments of the level of glucose in blood can be achieved either by discrete injections of insulin or, in severe cases, by an implanted insulin pump or artificial pancreas. The amount and frequency of insulin administration is determined by frequent or, preferably, continuous testing of the level of glucose in blood (i. e., blood glucose level).
Precise control of blood glucose level in the xe2x80x9cnormal rangexe2x80x9d, 60 mg/dL to 120 mg/dL, is necessary for Type I and Type II diabetics to avoid or reduce complications resulting from hypoglycemia and hyperglycemia. To achieve this level of control, the American Diabetes Association recommends that diabetics test their blood glucose level five times per day when the control of blood glucose level is necessary. Thus, there is a need for accurate and frequent or, preferably, frequent glucose monitoring to combat the effects of diabetes.
Conventional measurements of blood glucose level in a hospital or a physician""s office rely on the withdrawal of a 5 mL to 10 mL blood sample from the patient for analysis. This method is slow and painful and cannot be used for frequent glucose monitoring. An additional problem for hospitals and physicians"" offices is the disposal of testing media that are contaminated by blood.
Portable personal glucose meters are the most popular devices for monitoring blood glucose levels. Typically, a drop of blood is obtained by sticking a patient""s finger with a sharp object, and the blood obtained is analyzed by means of chemical reactions on a strip. These reactions provide an optical or electrochemical signal. This type of device provides a convenient way to monitor blood glucose level. However, the pain associated with collecting samples of blood, the potential contamination at the puncturing site, the disposal of biohazardous testing materials, the cumbersome procedures, and the chance of making mistakes often prevent patients from using the meters as frequently as recommended by physicians.
Implantable biosensors have also been proposed for glucose measurement. (G. S. Wilson, et al., xe2x80x9cProgress toward the development of an implantable sensor for glucosexe2x80x9d, Clin. Chem., Vol. 38 (1992), pages 1613-1617). These biosensors are electrochemical devices having enzymes immobilized at the surface of an electrochemical transducer. They are usually implanted into a patient""s tissue by means of a surgical procedure.
All of the foregoing categories of glucose monitoring techniques have one feature in common: they all involve a procedure whereby the skin of a human body part is disrupted by means of a mechanical device. These techniques are referred to as invasive techniques.
xe2x80x9cNon-invasivexe2x80x9d (alternatively referred to herein as xe2x80x9cNIxe2x80x9d) glucose-monitoring techniques measure in vivo glucose concentrations without collecting a blood sample. As defined herein, a xe2x80x9cnon-invasivexe2x80x9d technique is one that can be used without removing a sample from, or without inserting any instrumentation into, the tissues. The concept upon which most such technologies are based involves irradiating a vascular region of the body with electromagnetic radiation and measuring the spectral information that results from at least one of four primary processes: reflection, absorption, scattering, and emission. The extent to which each of these processes occurs is dependent upon a variety of factors, including the wavelength and polarization state of the incident radiation and the concentration of analytes in the body part. Concentrations of an analyte, e. g., glucose, are determined from the spectral information by comparing the measured spectra to a calibration curve or by reference to a physical model of the tissue under examination. Various categories of non-invasive measurement techniques will now be described.
NI techniques that utilize the absorption of infrared radiation can be divided into three distinct wavelength regimes: Near-infrared (NIR), mid-infrared (MIR) and far-infrared (FIR). As defined herein, NIR involves the wavelength range from about 600 nm to about 1300 nm, MIR involves the wavelength range from about 1300 nm to about 3000 nm, and FIR involves the wavelength range from about 3000 nm to about 25000 nm. As defined herein, xe2x80x9cinfraredxe2x80x9d (or IR) is taken to mean a range of wavelengths from about 600 nm to about 25000 nm.
U.S. Pat. Nos. 5,086,229; 5,324,979; and 5,237,178 describe non-invasive methods for measuring blood glucose level involving NIR radiation. In general, a blood-containing body part (e. g., a finger) is illuminated by one or more light sources, and one or more detectors detect the light that is transmitted through the body part. A blood glucose level is derived from a comparison to reference spectra for glucose and background interferents.
Due to the highly scattering and absorption nature of the human skin and tissue, light in the 600 nm to 1300 nm spectral range penetrates the skin and underlying tissues to different depths. The penetration depth depends on the wavelength of light and positioning of the source and detector. Analyzing the reflected or transmitted signal without accounting for the effect of different layers of skin can lead to erroneous estimates of the optical properties of the tissue and hence, the concentration of metabolites determined from these measured properties. The stratum corneum, epidermis, dermis, adipose tissue, and muscle layers can all interact with light and contribute to the measured signals. Controlling the penetration depth of the light and understanding the effect of the different layers of the skin on the generated signal are important for the non-invasive determination of metabolites in tissues. This NIR spectral region has been used for determination of blood oxygen saturation, hemoglobin, hematocrit, and tissue fat content. It is also used for exciting and detecting compounds in photodynamic therapy. At longer wavelengths, water absorption bands dominate tissue spectra. There are some narrower spectral windows in the 1500 nm to 1900 nm range and the 2100 nm to 2500 nm range, where both in vitro and in vivo tissue measurements were performed.
Light striking a tissue will undergo absorption and scattering. Most of the scattered photons are elastically scattered, i. e., they have the same frequency as the incident radiation (Rayleigh scattering). A small fraction of the scattered light (less than one in a thousand incident photons) is inelastically scattered (Raman scattering). Unless otherwise indicated herein, xe2x80x9cscatteringxe2x80x9d refers to elastic scattering.
Because of the multiple scattering effect of tissue, optical measurements, whether in transmission or reflectance, will contain tissue scattering information, as well as absorption information. Tissue scattering information includes cell size and cell shape, depth of the tissue layer in which scattering occurs, and refractive index of intracellular fluids and extracellular fluid. Absorption information includes absorption by tissue components, such as hemoglobin, melanin, and bilirubin, and the overtone absorption of water, glucose, lipids, and other metabolites.
Spatially resolved diffuse reflectance (SRDR) techniques are a subset of the elastic scattering methods previously described. In a typical example of a SRDR technique, as shown in FIG. 1A, light is introduced into the surface of a tissue sample, such as a body part, at an introduction site. The diffusely reflected light is measured at two or more detection sites located on the surface of the sample (e. g., the skin) at different distances, r, from the introduction site. The dependence of the intensity of the diffusely reflected light, i. e., reflectance R, as a function of the detection distance (r) is used to derive scattering and absorption coefficients of the tissue sample. These coefficients, in turn, are related to the concentration of analyte(s). Spatially resolved diffuse reflectance techniques have been described by L. Reynolds et al., xe2x80x9cDiffuse reflectance from a finite blood medium: application to the modeling of fiber optic cathetersxe2x80x9d, Applied Optics, Vol. 15 (1976), pages 2059-2067. Another use and interpretation were given by R. A. J. Groenhuis et al., xe2x80x9cScattering and absorption of turbid materials determined from reflection measurements. 1: Theoryxe2x80x9d, Applied Optics, Vol. 22 (1983), pages 2456-2462. Yet another application of spatially resolved diffuse reflectance was the determination of compounds in tissue, M. S. Patterson et al., xe2x80x9cQuantitative reflectance spectrophotometry for the noninvasive measurement of photosensitizer concentration in tissue during photodynamic therapyxe2x80x9d, SPIE (Society for Photooptical Instrument Engineering) Proceedings, Vol. 1065 (1989), pages 115-122. Other recent publications include: B. Chance, H. Liu, T. Kitai, Y. Zhang, xe2x80x9cEffect of solutes on the optical properties of biological materialsxe2x80x9d, Analytical Biochemistry, Vol. 227 (1995), pages 351-362; H. Liu, B. Beauvoit, M. Kimura, B. Chance, xe2x80x9cEffect of solutes on optical properties of biological materials: Models, cells and tissuesxe2x80x9d, Journal of Biomedical Optics, Vol. 1 (1996), pages 200-211; and J. Qu, B. Wilson, xe2x80x9cMonte Carlo modeling studies of the effect of physiological factors and other analytes on the determination of glucose concentration in vivo by near infrared optical absorption and scattering measurementsxe2x80x9d, Journal of Biomedical Optics, Vol. 2 (1997), pages 319-325.
Frequency-domain reflectance measurements use optical systems similar to those used for spatially resolved light scattering (reflectance (R) as a function of distance (r)), except that the light source is modulated at a high frequency and a synchronized detector is used (U.S. Pat. Nos. 5,187,672 and 5,122,974). The difference in phase angle and modulation between the incident beam of light and the reflected beam of light is used to calculate the scattering coefficient and the absorption coefficient of the tissue or scattering medium. U.S. Pat. No. 5,492,769 describes frequency domain method and apparatus for the determination of a change in the concentration of an analyte, and U.S. Pat. No. 5,492,118 describes a method and apparatus for determination of the scattering coefficient of tissues.
U.S. Pat. No. 6,070,093, issued May 30, 2000, assigned to the assignee of this application, describes a multiplex sensor that combines at least two NI measurements in order to compensate for the effects of spectral and physiological variables. Co-pending U.S. application Ser. No. 09/080,470, filed May 18, 1998, assigned to the assignee of this application, describes a non-invasive glucose sensor employing a temperature control. One purpose of controlling the temperature is to minimize the effect of physiological variables.
Although a variety of spectroscopic techniques have been disclosed in the art, there is still no commercially available device that provides non-invasive glucose measurements with an accuracy that is comparable to invasive methods. Signals obtained by prior art methods reflect the analyte information of the tissue as if the tissue comprised a single uniform layer. The signals, however, are vulnerable to the effects of surface layers of the skin, which are significantly different from the deeper layers of the skin in terms of textures, colors, and other properties. Also, prior art methods fail to address the effect of variations in efficiency of optical coupling between the measuring device and the skin. As a result, current approaches to non-invasive metabolite testing, such as glucose monitoring, have not achieved acceptable precision and accuracy.
Thus, there is a continuing need for improved NI instruments and methods that are unaffected by variations in skin structures and layers or account for the effect of skin layers. There is also a need for instruments with simple calibration schemes that can be set in the factory and periodically checked for accuracy in the field.
This invention involves a method and apparatus for non-invasively measuring at least one parameter of a sample of tissue, such as the absorption coefficient or the scattering coefficient of a layer of skin. Such parameters can be used to determine the concentration of an analyte of interest in the sample of tissue. As will be described more fully below, the present invention measures light that is reflected, scattered, absorbed, or emitted by the sample of tissue from a first pair of average sampling depths, dav1, dav2 and from at least one other pair of average sampling depths dav3, dav4, where dav3 and dav4 are greater than dav2 and dav1. These average sampling depths are preferably less than 3 mm, more preferably less than 2 mm. Confining the sampling depth in the tissue is achieved by appropriate selection of the distance separating the site at which light is introduced into the sample and the site at which light is collected from the sample after being reflected, scattered, absorbed, or emitted by the sample.
Confining the sampling depth in the tissue provides several advantages. First, confining the sampling depth allows determinations of the optical properties of a specific layer of the sample, e.g., epidermis, and decreases interference from other layers, e. g., stratum corneum, in these determinations. Secondly, the tissue region that is sampled can be more homogeneous than the tissue regions sampled by the devices described in prior art. Thirdly, the signal is obtained from a region of tissue having a substantially uniform temperature. Accordingly, the signal is not likely to be affected by the temperature gradient running from the surface of the tissue into the interior of the tissue.
In the preferred embodiments, this invention involves a method and apparatus for non-invasively measuring at least one parameter of a sample by means of a light introduction site and a plurality of light collection sites, each light collection site comprising a plurality of light collecting elements. The site at which light is introduced into the sample and the sites at which the light reflected, scattered, absorbed, or emitted by the sample is collected for detection occupy a small area on the surface of the tissue. The minimum distance between the site at which light is introduced into the sample and the closest site at which the light is collected is approximately equal to or less than the transport mean free path of a photon in the sample. The transport mean free path is the average distance that a photon can be propagated in a sample without undergoing an absorption event or a scattering event. This minimum distance is on the order of 1 mm for light in the near infrared region of the electromagnetic spectrum in typical samples of tissues. The maximum distance between the site at which light is introduced into the sample and any site at which the light is collected should be less than ten times that of the transport mean free path of a photon in the sample. This maximum distance is on the order of 1 cm for light in the near infrared region of the electromagnetic spectrum in typical samples of tissues. Preferably, the minimum distance between the site at which light is introduced into the sample and the closest site at which the light re-emitted from the sample is collected is less than 0.5 mm, and the maximum distance between the site at which light is introduced into the sample and the furthest site at which the light re-emitted from the sample is collected is less than 6 mm.
In one aspect, this invention involves a method for determining at least one optical parameter of a sample having a plurality of layers, wherein the layers have different properties. The method comprises the steps of:
a) introducing a beam of light into the sample at a light introduction site on a surface of the sample;
b) determining the intensities of light re-emitted from the sample at a plurality of light collection sites on the surface of the sample, at least a first light collection site collecting light re-emitted mainly from a first layer of the sample, at least a second light collection site collecting light re-emitted mainly from a second layer of the sample, the first light collection site being at a first distance from the light introduction site, and the second light collection site being at a second distance from the light introduction site, the first distance being less than said second distance;
c) determining at least one optical parameter of the first layer of the sample; and
d) determining at least one optical parameter of the second layer of the sample, the first layer having an average depth, as measured from the surface of the sample, of smaller magnitude than the average depth of the second layer, as measured from the surface of the sample.
In a preferred embodiment of this aspect, the method of this invention for measuring at least one optical parameter of a sample having layers having differing properties comprises the steps of:
a) introducing a beam of light into the sample at a light introduction site;
b) collecting light re-emitted from the sample at a plurality of light collection sites, wherein each of the light collection sites comprises at least two light collecting elements and each of the light collection sites is located at a different distance from the light introduction site;
c) determining the intensity of the light re-emitted at a first light collecting element of a light collection site located at a first distance from the light introduction site and the intensity of the light re-emitted at at least a second light collecting element of the light collection site located at the first distance from the light introduction site;
d) determining the absorption coefficient and the scattering coefficient of the sample at a given depth of the sample by means of a mathematical relationship between intensity of the light re-emitted at the first light collecting element of the light collection site located at the first distance from the light introduction site and intensity of the light re-emitted at at least a second light collecting element of the light collection site located at the first distance from the light introduction site;
e) determining the intensity of the light re-emitted at a first light collecting element of a light collection site located at a second distance from the light introduction site and the intensity of said light re-emitted at at least a second light collecting element of the light collection site located at the second distance from the light introduction site, wherein the second distance is greater than the first distance;
f) determining the absorption coefficient and the scattering coefficient of the sample at a greater depth of the sample than that of step d) by means of a mathematical relationship between intensity of the light re-emitted at the first light collecting element of the light collection site located at the second distance from the light introduction site and intensity of the light re-emitted at at least a second light collecting element of the light collection site located at the second distance from the light introduction site.
Depending upon the number of layers in a sample, the total number of light collection sites may vary. At a minimum, the number of light collection sites should be equal to the number of layers. Also, the separation between a particular light collection site and the light introduction site is determined by the depth and thickness of the particular layer in the sample for which this light collection site is designated. A minimum of two light collecting elements should be included in each light collection site.
In order to provide for the mathematical relationships in steps d) and f), in any light collection site of light collecting elements, the first light collecting element in the light collection site and at least a second light collecting element in the light collection site must be located at different distances from the light introduction site.
One example of the mathematical relation between the light collected at a first light collecting element at a first collection site (R1) and the light collected at at least a second light collecting element at the first collection site (R2) is the logarithm of 1/R1 as a function of corresponding logarithm of R1/R2. The mathematical relationship can be used to determine the absorption and scattering coefficients of the layer of tissue close to the surface of the sample (stratum corneum and epidermis) from the measured reflectance values and a calibration procedure based on known reflectance values.
One possible calibration procedure involves construction of a calibration diagram by plotting the measured values of a function of reflectance at one light collection site distance, e. g., f(1/R1), versus the measured values of another function of reflectance, e. g., f(R1/R2), at that light collection site distance for a series of materials of known measured absorption and scattering coefficients. These materials can be selected from solid plastic disks containing different levels of scattering and absorbing pigments, opaque or translucent glass, liquid suspensions of scattering materials, or the like. From the calibration diagram obtained, one can determine the scattering and absorption coefficients of an unknown sample based on its measured values of R1 and R2. Knowledge of the scattering and absorption coefficients can be used to determine the concentration of an analyte of interest in the layer of tissue close to the surface of the sample. The procedure described above can be repeated for layers of tissue that are located below the layer of tissue close to the surface of the sample. The method of this invention can be applied to any tissue comprising, in effect, two or more layers.
The method of this invention is also applicable for an arrangement wherein a single light collection site and a plurality of light introduction sites are employed. In this variation, the method is also capable of determining at least one optical parameter of a sample having a plurality of layers, wherein each of the layers has different properties. The method comprises the steps of:
a) introducing a plurality of beams of light into a sample at a plurality of light introduction sites on a surface of the sample, a first light introduction site being at a first distance from a light collection site on the surface of the sample, a second light introduction site being at a second distance from the light collection site on the surface of the sample, the first distance being less than the second distance;
b) determining the intensities of light re-emitted from the sample at the light collection site, the light collection site collecting light re-emitted mainly from a first layer of the sample and collecting light re-emitted mainly from a second layer in the sample, the light re-emitted from the first layer being introduced at the first light introduction site, the light re-emitted from the second layer being introduced at the second light introduction site;
c) determining at least one optical parameter of a the first layer of the sample; and
d) determining at least one optical parameter of the second layer of the sample, the first layer having an average depth, as measured from the surface of the sample, of smaller magnitude than the average depth of the second layer, as measured from the surface of the sample.
In a preferred embodiment of this variation, the method is also capable of determining at least one optical parameter of a sample having layers having different properties. The method comprises the steps of:
a) introducing beams of light into the sample at a plurality of light introduction sites, wherein each of the light introduction sites comprises at least two illuminating elements, each of the light introduction sites located at a different distance from a light collection site;
b) collecting light re-emitted from the sample at the light collection site;
c) determining the intensity of the re-emitted light resulting from illumination by a first illuminating element of a light introduction site located at a first distance from the light collection site and the intensity of the re-emitted light resulting from illumination by at least a second illuminating element of the light introduction site located at the first distance from the light collection site;
d) determining the absorption coefficient and the scattering coefficient of the sample at a given depth of the sample by means of a mathematical relationship between intensity of the re-emitted light resulting from illumination by the first illuminating element of the light introduction site located at the first distance from the light collection site and intensity of the re-emitted light resulting from illumination by at least a second illuminating -element of the light introduction site located at the first distance from the light collection site;
e) determining the intensity of the re-emitted light resulting from illumination by a first illuminating element of a light introduction site located at a second distance from the light collection site and the intensity of the re-emitted light resulting from illumination by at least a second illuminating element of the light introduction site located at a second distance from the light collection site, wherein the second distance is greater than the first distance;
f) determining the absorption coefficient and the scattering coefficient of the sample at a greater depth of the sample than that of step d) by means of a mathematical relationship between intensity of the re-emitted light resulting from illumination by the first illuminating element of the light introduction site located at the second distance from the light collection site and intensity of the re-emitted light resulting from illumination by at least a second illuminating element of the light introduction site located at the second distance from the light collection site.
In order to provide for the mathematical relationships in steps d) and f), in any light introduction site of light illuminating elements, the first illuminating element and at least a second illuminating element must be located at different distances from the light collection site.
Depending upon the number of layers in a sample, the total number of light introduction sites may vary. At a minimum, the number of light introduction sites should be equal to the number of layers. Also, the separation between a particular light introduction site and the light collection site is determined by the depth and thickness of the particular layer in the sample for which this light introduction site is designated. A minimum of two illuminating elements should be included in each light introduction site.
The present invention is particularly advantageous for samples of biological tissue where the presence of multiple layers of tissue, such as skin layers, may affect the result of determination of an optical parameter in a specific layer. Non-invasive measurements may be made on a body part of a patient, e. g., a finger, earlobe, lip, toe, skin fold, or bridge of the nose.
The invention offers several advantages over the prior art. The invention makes it is possible to determine the effect of layers having different optical properties in tissue-simulating phantoms and in human skin.
At small separations between the light introduction site and the light collection site, i. e., where the separation is close to the mean free path of the photon in tissue, the majority of light collected has penetrated the tissue to only a shallow depth. If the separation of the light introduction site from the light collection site ranges over large distances (e. g., 0.5 cm to 7 cm), reflected light collected at the light collection site has been propagated through the stratum corneum, epidermis, dermis, as well as deeper regions of tissue. The light path may also include the subcutis (which has higher fatty adipose tissue content) and underlying muscle structures. These layers provide sources of variability in measurements because of the heterogeneity in cell size, cell packing, blood content, as well as thermal properties.
Better temperature control can be achieved at the shallower depths of penetration in the sampled region. Smaller temperature gradients along the depth of a tissue are encountered when a temperature regulation means is applied (as described in co-pending U.S. application Ser. No. 09/080,470, filed May 18, 1998, incorporated herein by reference).
Furthermore, for tissue that is heterogeneous along dimensions substantially parallel to the surface of the skin, there is lower probability of photons encountering body components, such as hair, scar tissue, or vein structure, that will cause anomalies in the reflectance measurements. It is also possible to perform measurements on a small localized area of the skin with an optical instrument designed to have the light introduction site close to the light collection site rather than with a light introduction site that is located at a great distance from the light collection site. Thus, it is possible to detect blood vessels and hair fibers and determine their effect on the optical signals.
Optical instruments wherein the light introduction site is separated from the light collection site by a great distance require the use of a large body mass, such as the muscle of the arm, thigh, or the abdomen. Accordingly, the body locations where such an optical instrument can be used are limited, and substantial disrobing and inconvenience for the user are required. Thus, another advantage of the design of the apparatus of the present invention is that optical instruments wherein the distance from the light introduction site to the light collection site is 5 mm or less can be used, particularly with small body parts, such as ear lobes and fingers. However, optical instruments wherein the distance from the light introduction site to the light collection site is 5 mm or less can also be used with larger body parts, such as the forearm, thigh, or abdomen.
Another advantage of a small distance between light introduction site and the light collection site is the higher signal to noise ratio obtainable at small separations, due to increases in the amount of light ultimately reaching the detector. Thus simpler, inexpensive, rugged components, such as light emitting diodes, small flash lamps, and incandescent lamps, can be used as sources of light, and inexpensive commercially available photodiodes can be used as detectors. Optical instruments having a large separation between the light introduction site and the light collection site require laser diodes as source of light and photomultiplier tubes as detector, because weaker signals are generated.